Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D317/28—Radicals substituted by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D317/34—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings

Definitions

• the present invention relates to novel phenylalkyl sulfamate compounds, a muscle relaxation and a method for preventing or treating a disease associated with muscle spasm.
• Myotony or spasm is frequently observed as a sequel of head injuries, and is difficult to treat.
• Myotony is one of skeletal muscle dysfunctions resulting from muscle tone increase, and is caused by central nervous system damage due to wound and various other causes.
• the causes of muscle tone are abnormal posture, fatigue, degenerative change in spine, etc.
• Myotony can be induced by one of various causes including skeletal muscle spasticity and spastic paralysis causing serious hindrance to daily life.
• spastic paralysis involves symptoms such as tension of the hand and feet, stiffness, difficulty when walking, etc., and causes serious hindrance to daily life.
• Centrally acting muscle relaxants block receptors related to the excitement of skeletal muscle function, or excite receptors related to the inhibition of skeletal muscle function, in order to relax muscle tone or decrease excessively activated reflection function thus causing muscle relaxation.
• the centrally acting muscle relaxants may include methocarbaamol, chlormezanon, carisoprodol, eperisone, phenprobamide, etc.
• these drugs act on spinal cord interneurons to inhibit monosynapse and polysynapse, and thus, have side effects including central nervous system depression and muscle weakness.
• Muscle relaxants are used as an agent for improving symptoms including hernia of an intervertebral disk related to muscle spasm that is involved in skeletal muscle diseases, and vascular disorders of the spinal cord, spastic paralysis of the spinal cord, cervical spondylosis, cerebral palsy, sequelae of injuries(spinal cord injuries, head injuries), spinocerebellar degeneration, etc., and Muscle relaxants are also used as an adjuvant to anesthetic agents.
• R 3 , R4, Rs, 3 ⁇ 4 and R 7 are each independently selected from the group consisting of hydrogen, halogen, Q- C 5 alkyl group, nitro group and unsubstituted or C1-C3 alkyl-substituted amine group;
• Rs and R 9 are each independently hydrogen or C1-C3 alkyl group;
• n and m are each independently integer of 0-2.
• the present inventor has made intensive studies to develop a novel muscle relaxant with excellent activity and low toxicity which may be applied to effective treatment for various disease associated with muscle spasm. As results, the present inventors have discovered that the novel phenylalkyl sulfamate derivatives represented by above formula 1 provide highly enhanced muscle relaxation activity with significantly decreased side effects.
• alkyl refers to a straight or branched chain of saturated hydrocarbon group, e.g., methyl, ethyl, propyl, butyl, isobutyl, tert butyl and pentyl.
• C1-C5 alkyl group refers to an alkyl group with carbon number of 1-5.
• aryl refers to a totally or partially unsaturated monocylic or polycyclic carbon rings having aromaticity.
• the aryl group of the present invention is preferably monoaryl or biaryl.
• cycloalkyl refers to a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms.
• Ri and R 2 are each independently selected from the group consisting of hydrogen, CrC 3 alkyl group and phenyl group or Ri and R 2 together with the carbon atom to which they attach form C 5 -C 6 cycloalkyl group, and wherein R 1 and R 2 are not hydrogen at the same time.
• R 3 , R,, R 5 , R6 and R 7 are each independently selected from the group consisting of hydrogen, chlorine, fluorine, iodine, Ci-C 3 alkyl group, nitro group and unsubstituted or methyl-substituted amine group.
• n and m are each independently integer of 0-1.
• the compound is selected from the group consisting of:
• the compound is selected from the group consisting of:
• the compound is in the form of racemate, enantiomer, diastereomer, a mixture of enantiomer or a mixture of diastereomer.
• the present inventors have synthesized the compounds of various stereochemistries, and investigated their muscle relaxation activity by multilateral experiments.
• enantiomer refers to one of two stereoisomers that are mirror images of each other which are non-superposable due to existence of one or more chiral carbons.
• the enantiomer of the present invention is one in which chiral carbons of G, and C 5 are diverse in stereo-configuration.
• diastereomer refers to stereoisomers that are not enantiomers, which occurs when two or more stereoisomers of a compound have different configurations at one or more (but not all) of the equivalent chiral centers thus are not mirror images of each other.
• racemate refers to one that has equal amounts of two enantiomers of different stereo-configuration, and lack in optical activity.
• the pharmaceutically acceptable salt is produced by reacting the compound with an inorganic acid, an organic acid, an amino acid, sulfonic acid, an alkali metal or ammonium ion.
• the pharmaceutically acceptable salts of the present invention are those which can be manufactured by using a method known in the art, for example, but not limited to, salts with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphate, nitrate and carbonate; and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid and acetylsalicylic acid (aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, and proline; salt
• a method for muscle relaxation comprising administering pharmaceutically effective amount of the compound of the present invention or pharmaceutically acceptable salt thereof to a subject in need thereof.
• the present inventor has observed that administration of the compound of the present invention significantly increased grip strength and residence time on rotarod rotating of mice, suggesting that the compound of the present invention may be effectively used for improving muscle relaxation activity.
• a method for preventing or treating a disease associated with muscle spasm comprising administering pharmaceutically effective amount of the compound of the present invention or pharmaceutically acceptable salt thereof to a subject in need thereof.
• the compound of the present invention has a superior activity for muscle relaxation with low toxicity. Therefore, it has potential to be developed as a therapeutic agent for preventing and treating various diseases associated with muscle spasm.
• disease associated with muscle spasm refers to a disease or disorder resulted from muscle spasm caused by dysfunctional muscle relaxation or excessive muscle tone; or disease or disorder inducing muscle spasm.
• muscle spasm As used herein, “muscle spasm” is used interchangeably with “myotony”.
• the disease associated with muscle spasm is selected from the group consisting of herniation of intervertebral disk, vascular disorders of the spinal cord, spastic spinal paralysis, cervical spondylosis, cerebral palsy, sequelae of spinal cord injuries, sequelae of head injuries.
• composition for preventing or treating a disease associated with muscle spasm comprising the compound of the present invention or pharmaceutically acceptable salt thereof as an active ingredient.
• pharmaceutically effective amount refers to an amount enough to show and accomplish efficacies and activities for preventing, alleviating, treating a disease associated with muscle spasm.
• the pharmaceutical composition of this invention includes a pharmaceutically acceptable carrier besides the active ingredient compound.
• the pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention which is commonly used in pharmaceutical formulations, but is not limited to, includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, rubber arable, potassium phosphate, arginate, gelatin, potassium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oils.
• the pharmaceutical composition according to the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, and a preservative.
• a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mann
• the pharmaceutical composition according to the present invention may be administered orally or parenterally, and concretely, administered parenterally.
• parenteral administration it may be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, transdermal ⁇ or intra-articularly. More concretely, it is administered intramuscularly or intraperitoneally.
• a suitable dosage amount of the pharmaceutical composition of the present invention may vary depending on pharmaceutical formulation methods, administration methods, the patient's age, body weight, sex, pathogenic state, diet, administration time, administration route, an excretion rate and sensitivity for a used pharmaceutical composition.
• pharmaceutical composition of the present invention may be administered with a daily dosage of 0.001-10000 mg/kg (body weight).
• the pharmaceutical composition according to the present invention may be formulated with pharmaceutically acceptable carrier and/or vehicle as described above, finally providing several forms including a unit dose form and a multi-dose form.
• the formulations include, but not limited to, a solution, a suspension or an emulsion in oil or aqueous medium, an elixir, a powder, a granule, a tablet and a capsule, and may further comprise a dispersion agent or a stabilizer.
• sulfamation refers to a reaction in which a sulfamate group is substituted on a hydroxyl group of an alcohol. Sulfamation may be performed by various reagents including, but not limited to, chlorosulfonyl isocyanate, sulfamide and sulfuryl chloride.
• the method further comprises reacting a compound represented by the following formula 5: with and acid and a compound represented by the following formula 6-1 or formula 6-2 to form the compound of formula 4: wherein Ri to R 7 , n, m and A are same as defined in formula 4
• the acid of the present invention is used for protonations on methoxy groups in the compound of formula 6-1 or on carbonyl oxygen in the compound of formula 6-2 such that resultant methanols or water may leave well when diol of the compound of formula 5 reacts with the compound of formula 6-1 or 6-2.
• the method further comprises performing dihydroxylation of a compound represented by the following formula 7: mpound of formula 5, wherein 3 to R 7 , n, m and A are same as defined in formula 4.
• dihydroxylation refers to a reaction in which an oxidant is added to alkenes to form vicinal diols. Concretely, the dihydroxylation is performed by syn-addition of two hydroxyl groups to an alkene.
• the dihydroxylation may be performed by oxidant including, but not limited to, Os0 4 , K 2 0s0 4 , and KMn0 4 .
• the method further comprises performing dihydroxylation of a compound represented by the following formula 7: with an oxidant to form the compound of formula 5, wherein R 3 to R 7 , n, m and A are same as defined in formula 4.
• dihydroxylation refers to a reaction in which an oxidant is added to alkenes to form vicinal diols. Concretely, the dihydroxylation is performed by syn-addition or anti-addition of two hydroxyl groups to an alkene.
• the dihydroxylation may be performed by oxidant including, but not limited to, Os0 4 , K 2 0s0 4 , K 2 C0 3 and KMn0 4 .
• a dioxolan-alcohol compound used in the synthesis of a sulfamate compound is synthesized by dihydroxylation, condensation and a deprotection reaction.
• Preparation example 13 ((4R,5R)-5-(2-fluorophenyl)-2,2-dimethyl-l,3- dioxolan-4-yl)methanol
• (1R, 2R)-l-(2-fluorophenyl)-3-(methoxymethoxy)propane- l,2-diol(Preparation example 12) was used instead of (1R, 2R)-l-(2-chlorophenyl)-3- (methoxymethoxy)propane-l,2-diol(Preparation example 3), to obtain the title compound (1.73g, 30 ⁇ 40%).
• Dichloromethane(DMC) was added to (2S,3R)-methyl-3-(2-chlorophenyl)-2,3- dihydroxypropanoate(24.4g, Preparation example 25) and cooled to 0 ° C .
• 2,2- Dimethoxypropane (26ml, 211.77mmol) and p-toluenesulfonic acid (2g, 10.58mmol) was added and stirred at room temperature.
• the reaction mixture was quenched with H 2 0, extracted with DCM, washed with H 2 0, dried over anhydrous magnesium sulfate, filtered and concentrated.
• the crude compound was purified by a silica gel column to produce the title compound(23.6g, 70 ⁇ 95%).
• Example 64 The substantially same method as described in Example 64 was conducted, except that (2S,3R)-methyl-3-(2-chlorophenyl)-2.3-dihydroxypropanote(Preparation example 25) was used instead of (2S,3R)-methyl-3-(2-chlorophenyl)-2 J-dihydroxypropanote , to obtain the title compound(1.4g, 70 ⁇ 95%).
• Example 65 The substantially same method as described in Example 65 was conducted, except that (4S,5R)-methyl-5-(2-chlorophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate (Preparation example 66) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)- 2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 64), to obtain the title compound(2.2g, 70 ⁇ 95%)
• Example 65 The substantially same method as described in Example 65 was conducted, except that (2R, 3S)-methyl-3-(2-chlorophenyl)-l,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 68) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)- 2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 64), to obtain the title compound (1.7g, 70 ⁇ 95%)
• Example 68 The substantially same method as described in Example 68 was conducted, except that (2S,3R)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate was used instead of (2R,3S)-methyl-3-(2-chlorophenyl)-2,3-dihydroxypropanoate, to obtain the title compound(1.5g, 70 ⁇ 95%).
• Example 65 The substantially same method as described in Example 65 was conducted, except that (2R, 3S)-methyl-3-(2-chlorophenyl)-2-phenyl-l,3-dioxolane-4-carboxylate (Preparation example 76) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)-
• Example 65 The substantially same method as described in Example 65 was conducted, except that (2S, 3R)-methyl-3-(2-chlorophenyl)-2-phenyl-l,3-dioxolane-4-carboxylate (Preparation example 78) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)- 2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 64), to obtain the title compound(1.3g, 70 ⁇ 95%)
• Example 89 The substantially same method as described in Example 88 was conducted, except that (4S,5R)-methyl-5-(2-fluorophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate (Preparation example 89) was used instead of (4R,5S)-methyl-5-(2-fluorophenyl)- 2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 87), to obtain the title compound(2.2g, 70 ⁇ 95%)
• Example 87 The substantially same method as described in Example 87 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.1g, 70 ⁇ 95%).
• Example 65 The substantially same method as described in Example 65 was conducted, except that (2R, 3S)-methyl-3-(2-fluorophenyl)-l,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 91) was used instead of (4R,5S)-methyl-5-(2-chlorophenyl)- 2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 64), to obtain the title compound(1.9g, 70 ⁇ 95%)
• Example 91 The substantially same method as described in Example 91 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(1.7g, 70 ⁇ 95%).
• Example 96 The substantially same method as described in Example 96 was conducted, except that (2S, 3R)-methyl-3-(2-fluorophenyl)-l,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation example 97)was used instead of (2R, 3S)-methyl-3-(2-fluorophenyl)- l,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation example 95), to obtain the title compound(1.5g, 70 ⁇ 95%)
• Example 87 The substantially same method as described in Example 87 was conducted, except that benzaldehyde was used instead of 3-pentanone, to obtain the title compound (1.6g, 50 ⁇ 70%).
• Example 25 The substantially same method as described in Example 25 was conducted, except that (E)-methyl-3-(2-iodophenyl)acrylate (Preparation example 103) was used instead of (E)-Methyl-3-(2-chlorophenyl)acrylate (Preparation example 24), to obtain the title compound (3. lg, 60 ⁇ 80%).
• Example 107 The substantially same method as described in Example 107 was conducted, except that (4S,5R)-methyl-5-(2-iodophenyl)-2-mehtyl-1.3-dioxolane-4-carboxylate (Preparation example 108) was used instead of (4R,5S)-methyl-5-(2-iodophenyl)-2- mehtyl-1.3-dioxolane-4-carboxylate(Preparation example 106), to obtain the title compound (1.9g, 70 ⁇ 95%)
• Example 107 The substantially same method as described in Example 107 was conducted, except that (4R,5S)-methyl-5-(2-iodophenyl)-2,2-d ' iehtyl-1.3-dioxolane-4-carboxylate (Preparation example 110) was used instead of (4R,5S)-methyl-5-(2-iodophenyl)-2- mehtyl-1.3-dioxolane-4-carboxylate(Preparation example 106), to obtain the title compound(2.1g, 70 ⁇ 95%)
• Example 105 The substantially same method as described in Example 110 was conducted, except that (2S,3R)-methyl-3-(2-iodophenyl)-2,3-dihydroxypropanoate (Preparation example 105) was used instead of (2R,3S)-methyl-3-(2-iodophenyl)-2,3- dihydroxypropanoate (Preparation example 104), to obtain the title compound (2.3g, 60 ⁇ 85%).
• Example 112 The substantially same method as described in Example 107 was conducted, except that (4S,5R)-methyl-5-(2-iodophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate (Preparation example 112) was used instead of (4R,5S)-methyl-5-(2-iodophenyl)-2- mehtyl-1.3-dioxolane-4-carboxylate(Preparation example 106), to obtain the title compound(1.8g, 70 ⁇ 95%)
• Example 112 The substantially same method as described in Example 112 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.9g, 70 ⁇ 95%).
• Example 114 The substantially same method as described in Example 114 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (1.9g, 70 ⁇ 95%).
• Example 116 The substantially same method as described in Example 116 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (2.3g, 70 ⁇ 95%).
• Example 118 The substantially same method as described in Example 118 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the title compound(1.9g, 50 ⁇ 70%).
• Example 120 The substantially same method as described in Example 120 was conducted, except benzaldehyde that was used instead of cyclohexanone, to obtain the title compound (2.1g, 50 ⁇ 70%).
• Example 132 The substantially same method as described in Example 131 was conducted, except that (4S,5R)-methyl-5-(2,4-dichlorophenyl)-2,2-diehtyl-1.3-dioxolane-4- carboxylate (Preparation example 132) was used instead of ((4R,5S)-methyl-5-(2,4- dichlorophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate (Preparation example 130), to obtain the title compound (1.2g, 70 ⁇ 95%).
• Example 132 The substantially same method as described in Example 132 was conducted, except that cydopentanone was used instead of 3-pentanone, to obtain the title compound (2.2g, 70 ⁇ 95%).
• Example 135 The substantially same method as described in Example 135 was conducted, except that (2S,3R)-methyl-3-(2,4-dichlorophenyl)-l,4-dioxaspiro[4,4]nonane-2- carboxylate (Preparation example 136) was used instead of (2R, 3S)-methyl-3-(2,4- dichlorophenyl)-l,4-dioxaspiro[4,4]nonane-2-carboxylate(Preparation example 134), to obtain the title compound(1.2g, 70 ⁇ 95 )
• Example 134 The substantially same method as described in Example 134 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(1.8g, 70 ⁇ 95%).
• Example 136 The substantially same method as described in Example 136 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(1.6g, 70 ⁇ 95%).
• Example 152 The substantially same method as described in Example 151 was conducted, except that (4S,5R)-ethyl-5-(2,6-dichlorophenyl)-2,2-diehtyl-1.3-dioxolane-4- carboxylate (Preparation example 152) was used instead of (4R,5S)-ethyl-5-(2,6- dichlorophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 150), to obtain the title compound(2.1g, 70 ⁇ 95%)
• Example 150 The substantially same method as described in Example 150 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.1g, 70 ⁇ 95%).
• Example 152 The substantially same method as described in Example 152 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.5g, 70 ⁇ 95%).
• Example 155 The substantially same method as described in Example 155 was conducted, except that (2S,3R)-ethyl-3-(2,6-dichlorophenyl)-l,4-dioxaspiro[4,4]nonane-2- carboxylate (Preparation example 156)was used instead of (2R, 3S)-ethyl-3-(2,6- dichlorophenyl)-l,4-dioxaspiro[4,4]nonane-2-carboxylate(Preparation example 154), to obtain the title compound (2.0g, 70 ⁇ 95%)
• Example 154 The substantially same method as described in Example 154 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (2.2g, 70 ⁇ 95%).
• Example 155 The substantially same method as described in Example 155 was conducted, except that (2R,3S)-ethyl-3-(2,6-dichlorophenyl)-l,4-dioxaspiro[4,5]decane-2- carboxylate (Preparation example 158) was used instead of (2R, 3S)-ethyl-3-(2,6- dichlorophenyl)-l,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 154), to obtain the title compound(1.7g, 70 ⁇ 95%)
• Example 156 The substantially same method as described in Example 156 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (1.9g, 70 ⁇ 95%).
• Example 158 The substantially same method as described in Example 158 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the title compound (2.0g, 50 ⁇ 70%).
• Example 159 The substantially same method as described in Example 159 was conducted, except that (2R, 3S)-ethyl-3-(2,6-chlorophenyl)-2-phenyl-l,3-dioxolane-4-carboxylate (Preparation example 162) was used instead of (2R, 3S)-ethyl-3-(2,6- dichlorophenyl)-l,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation example 158), to obtain the title compound (1.6g, 70 ⁇ 95%)
• Example 167 The substantially same method as described in Example 167 was conducted, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2-mehtyl-1.3-dioxolane-4-carboxylate (Preparation example 168) was used instead of (4R,5S)-methyl-5-(2-nitrophenyl)-2- mehtyl-1.3-dioxolane-4-carboxylate(Preparation example 166), to obtain the title compound(1.6g, 70 ⁇ 95%)
• Example 167 The substantially same method as described in Example 167 was conducted, except that (4R / 5S)-methyl-5-(2-nitrophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate (Preparation example 170) was used instead of 4R,5S)-methyl-5-(2-nitrophenyl)-2- mehtyl-1.3-dioxolane-4-carboxylate (Preparation example 166), to obtain the title compound (1.9g, 70 ⁇ 95%)
• Example 172 The substantially same method as described in Example 171 was conducted, except that (4S,5R)-methyl-5-(2-nitrophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate (Preparation example 172) was used instead of (4R,5S)-methyl-5-(2-nitrophenyl)- 2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 170), to obtain the title compound(2.0g, 70 ⁇ 95%)
• Example 170 The substantially same method as described in Example 170 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.5g, 70 ⁇ 95%).
• Example 174 The substantially same method as described in Example 171 was conducted, except that (2R, 3S)-methyl-3-(2-nitrophenyl)-l,4-dioxaspiro[4,4]nonane-2- carboxylate (Preparation example 174) was used instead of (4R,5S)-methyl-5-(2- nitrophenyl)-2,2-diehtyl-1.3-dioxolane-4-carboxylate(Preparation example 170), to obtain the title compound (2. lg, 70 ⁇ 95%)
• Example 172 The substantially same method as described in Example 172 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.9g, 70 ⁇ 95%).
• Example 174 The substantially same method as described in Example 174 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (1.7g, 70 ⁇ 95%).
• Example 176 The substantially same method as described in Example 176 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(2.2g, 70 ⁇ 95%).
• Example 178 The substantially same method as described in Example 178 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the title compound (1.9g, 50 ⁇ 70%).
• Example 180 The substantially same method as described in Example 180 was conducted, except benzaldehyde that was used instead of cyclohexanone, to obtain the title compound (1.8g, 50 ⁇ 70%).
• Example 187 The substantially same method as described in Example 187 was conducted, except that (4R,5S)-methyl-2,2-diehtyl-5-o-tolyl-1.3-dioxolane-4-carboxylate (Preparation example 190) was used instead of (4R,5S)-methyl-2-mehtyl-5-o-tolyl- 1.3-dioxolane-4-carboxylate (Preparation example 186), to obtain the title compound (1.7g, 70 ⁇ 95%)
• Example 190 The substantially same method as described in Example 190 was conducted, except that (2S,3R)-methyl-3-(2-methylphenyl)-2,3-dihydroxypropanoate (Preparation example 57) was used instead of (2R,3S)-methyl-3-(2-methylphenyl)- 2,3-dihydroxypropanoate (Preparation example 54), to obtain the title compound (2.2g, 60 ⁇ 85%).
• Example 192 The substantially same method as described in Example 191 was conducted, except that (4S,5R)-methyl-2,2-diehtyl-5-o-tolyl-1.3-dioxolane-4-carboxylate (Preparation example 192) was used instead of (4R, 5S)-methyl-2,2-diehtyl-5-o-tolyl- 1.3-dioxolane-4-carboxylate (Preparation example 190), to obtain the title compound (1.8g, 70 ⁇ 95%)
• Example 190 The substantially same method as described in Example 190 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.1g, 70 ⁇ 95%).
• Example 194 The substantially same method as described in Example 191 was conducted, except that (2R, 3S)-methyl-3-o-tolyl-l,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 194) was used instead of (4R, 5S)-methyl-2,2-diehtyl-5-o-tolyl- 1.3-dioxolane-4-carboxylate(Preparation example 190), to obtain the title compound(1.6g, 70 ⁇ 95%)
• Example 192 The substantially same method as described in Example 192 was conducted, except that cyclopentanone was used instead of 3-pentanone, to obtain the title compound (2.5g, 70 ⁇ 95%).
• Example 195 The substantially same method as described in Example 195 was conducted, except that (2S, 3R)-methyl-3-o-tolyl-l,4-dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 196) was used instead of (2R, 3S)-methyl-3-o-tolyl-l,4- dioxaspiro[4,4]nonane-2-carboxylate(Preparation example 194), to obtain the title compound(2.0g, 70 ⁇ 95%)
• Example 194 The substantially same method as described in Example 194 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound (1.8g, 70 ⁇ 95%).
• Example 195 The substantially same method as described in Example 195 was conducted, except that (2R, 3S)-methyl-3-o-tosyl-l,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation example 198) was used instead of (2R, 3S)-methyl-3-o-tolyl-l,4- dioxaspiro[4,4]nonane-2-carboxylate (Preparation example 194), to obtain the title compound (1.5g, 70 ⁇ 95%)
• Example 196 The substantially same method as described in Example 196 was conducted, except that cyclohexanone was used instead of cyclopentanone, to obtain the title compound(2.2g, 70 ⁇ 95%).
• Example 199 The substantially same method as described in Example 199 was conducted, except that (2S, 3R)-methyl-3-o-tosyl-l,4-dioxaspiro[4,5]decane-2-carboxylate (Preparation example 200) was used instead of (2R, 3S)-methyl-3-o-tosyl-l,4- dioxaspiro[4,5]decane-2-carboxylate (Preparation example 198), to obtain the title compound (1.5g, 70 ⁇ 95%)
• Example 198 The substantially same method as described in Example 198 was conducted, except that benzaldehyde was used instead of cyclohexanone, to obtain the title compound (2.2g, 50 ⁇ 70%).
• Example 200 The substantially same method as described in Example 200 was conducted, except benzaldehyde that was used instead of cyclohexanone, to obtain the title compound (1.9g, 50 ⁇ 70%).
• Example 203 The substantially same method as described in Example 203 was conducted, except that (2S, 3R)-methyl-3-o-tosyl-2-phenyl-l,3-dioxolane-4-carboxylate (Preparation example 204) was used instead of (2R, 3S)-methyl-3-o-tosyl-2-phenyl- l,3-dioxolane-4-carboxylate (Preparation example 202), to obtain the title compound (1.3g, 70 ⁇ 95%)
• Example 46 The substantially same method as described in Example 46 was conducted, except that (4R, SSJ-methyl- ⁇ -dimethyl-S-phenyl-l ⁇ -dioxolane ⁇ -carboxylateCPreparation example 218) was used instead of (4R, 5S)-methyl-5-(2-nitrophenyl)-l,3-dioxolane- 4-carboxylate (Preparation example 45), to obtain the title compound(4.4g, 70 ⁇ 95%)
• Example 190 The substantially same method as described in Example 190 was conducted, except that (2R, 3S)-methyl-3-phenyl-2,3-dihydroxypropanoate(Preparation example 217) was used instead of (2R, 3S)-methyl-3-(2-methylphenyl)-2,3- dihydroxypropanoate (Preparation example 54), to obtain the title compound(1.9g, 70 ⁇ 95%)
• Example 219 The substantially same method as described in Example 219 was conducted, except that (4R, 5S)-methyl-2,2-diethyl-5-phenyl-l,3-dioxolane-4-carboxylate (Preparation example 223) was used instead of (4R, 5S)-methyl-2,2-dimethyl-5- phenyl-l,3-dioxolane-4-carboxylate(Preparation example 218), to obtain the title compound(1.3g, 70 ⁇ 95%)
• Example 224 The substantially same method as described in Example 224 was conducted, except that (4S, 5R)-methyl-2,2-dimethyl-5-phenyl-l,3-dioxolane-4-carboxylate (Preparation example 225) was used instead of (4R, 5S)-methyl-2,2-dimethyl-5- phenyl-l,3-dioxolane-4-carboxylate(Preparation example 218), to obtain the title compound(6.5g, 70 ⁇ 95%)
• Example 227 The substantially same method as described in Example 224 was conducted, except that (4R, 5S)-methyl-3-phenyl-l,4-dioxapiro[4,4]nonane-2-carboxylate (Preparation example 227) was used instead of (4R, 5S)-methyl-2,2-diethyl-5- phenyl-l,3-dioxolane-4-carboxylate (Preparation example 223), to obtain the title compound (0.7g, 70 ⁇ 95%)
• Example 224 The substantially same method as described in Example 224 was conducted, except that (4R, 5S)-methyl-3-phenyl-l,4-dioxapiro[4,5]decane-2-carboxylate (Preparation example 231) was used instead of (4R, 5S)-methyl-2,2-diethyl-5- phenyl-l,3-dioxolane-4-carboxylate(Preparation example 223), to obtain the title compound(1.0g, 70 ⁇ 95%)
• Example 217 The substantially same method as described in Example 217 was conducted, except that (E)-tert-butyldimethyl(5-phenylpent-3-enyloxy)silane(Preparation example 237) was used instead of (E)-Methyl cinnamate (Preparation example 216), to obtain the title compound(8.7g, 70 ⁇ 95%)
• Example 241 The substantially same method as described in Example 241 was conducted, except that (2-((4R,5R)-5-benzyl-2,2-dimethyl-l,3-dioxolan-4-yl)ethoxy)(tert- butyl)dimethylsilane(Preparation example 243) was used instead of (2-((4S,5S)-5- benzyl-2,2-dimethyl-l,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane(Prepa example 240), to obtain the title compound(7.4g, 80 ⁇ 95%)
• Example 253 The substantially same method as described in Example 252 was conducted, except that 2-((2R,3R)-3-benzyl-l,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 253) was used instead of 2-((2S,3S)-3-benzyl-l,4- dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 251), to obtain the title compound (0.8g, 80 ⁇ 95%)
• Example 254 The substantially same method as described in Example 254 was conducted, except that 2-((2S, 3S)-3-benzyl-l,4-dioxaspiro[4.5]decan-2-yl)ethyl pivalate (Preparation example 255) was used instead of 2-((2R,3R)-3-benzyl-l,4- dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 253), to obtain the title compound (l.Og, 80 ⁇ 95%)
• Example 240 The substantially same method as described in Example 240 was conducted, except that (2R, 3S)-methyl 2,3-dihydroxy-4-phenylbutanoate(Preparation example 260) was used instead of (2S,3S)-5-(tert-butyldimethylsilyloxy)-l-phenylpentane-2,3- diol(Preparation example 239), to obtain the title compound(3.1g, 70 ⁇ 95%)
• Example 234 The substantially same method as described in Example 234 was conducted, except that (4R,5S)-methyl 5-benzyl-2,2-dimethyl-l,3-dioxolane-4- carboxylate(Preparation example 261) was used instead of (4S, 5R)-methyl-3- phenyl-l,4-dioxapiro[4,5]decane-2-carboxylate (Preparation example 233), to obtain the title compound(2.3g, 70 ⁇ 95%)
• Example 264 The substantially same method as described in Example 264 was conducted, except that (2R, 3S)-methyl 3-benzyl-l,4-dioxaspiro[4.4]nonane-2-carboxylate (Preparation example 265) was used instead of (4R,5S)-methyl-5-benzyl-2,2- dimethyl-l,3-dioxolane-4-carboxylate(Preparation example 263), to obtain the title compound (0.8g, 70 ⁇ 95%)
• Example 262 The substantially same method as described in Example 262 was conducted, except that (4S,5R)-methyl-5-benzyl-2,2-dimethyl-l,3-dioxolane-4-carboxylate (Preparation example 270) was used instead of (4R,5S)-methyl 5-benzyl-2,2- dimethyl-l,3-dioxolane-4-carboxylate(Preparation example 261), to obtain the title compound (2.7g, 70 ⁇ 95%)
• Example 272 The substantially same method as described in Example 264 was conducted, except that (4S,5R)-methyl-5-benzyl-2,2-dimethyl-l,3-dioxolane-4-carboxylate (Preparation example 272) was used instead of (4R,5S)-methyl-5-benzyl-2,2- dimethyl-l,3-dioxolane-4-carboxylate (Preparation example 263), to obtain the title compound (1.2g, 70 ⁇ 95%)

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